US20130052262A1 - Dabigatran etexilate-containing oral pharmaceutical composition - Google Patents
Dabigatran etexilate-containing oral pharmaceutical composition Download PDFInfo
- Publication number
- US20130052262A1 US20130052262A1 US13/582,183 US201113582183A US2013052262A1 US 20130052262 A1 US20130052262 A1 US 20130052262A1 US 201113582183 A US201113582183 A US 201113582183A US 2013052262 A1 US2013052262 A1 US 2013052262A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical composition
- oral pharmaceutical
- composition according
- binder
- inorganic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000008203 oral pharmaceutical composition Substances 0.000 title claims abstract description 32
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 31
- 230000002378 acidificating effect Effects 0.000 claims description 29
- 239000011230 binding agent Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 19
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 11
- 150000007522 mineralic acids Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- -1 inorganic acid salt Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 5
- 239000011162 core material Substances 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 229960002089 ferrous chloride Drugs 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 235000011147 magnesium chloride Nutrition 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 150000008043 acidic salts Chemical class 0.000 description 9
- 239000000945 filler Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000000314 lubricant Substances 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 229910002012 Aerosil® Inorganic materials 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000007884 disintegrant Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 description 5
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 4
- 229920003085 Kollidon® CL Polymers 0.000 description 4
- 230000009477 glass transition Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000002156 adsorbate Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 229960005168 croscarmellose Drugs 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 2
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- FKLRQQKBKCAVNR-UHFFFAOYSA-N 2-(2-hydroxyacetyl)oxyacetic acid;sodium Chemical compound [Na].OCC(=O)OCC(O)=O FKLRQQKBKCAVNR-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- XFKCVDGCSPYQLP-UHFFFAOYSA-N CCCCCCOC(=O)NC(=N)C1=CC=C(NCC2=NC3=CC(C(=O)N(CCC(C)=O)C4=NC=CC=C4)=CC=C3N2C)C=C1 Chemical compound CCCCCCOC(=O)NC(=N)C1=CC=C(NCC2=NC3=CC(C(=O)N(CCC(C)=O)C4=NC=CC=C4)=CC=C3N2C)C=C1 XFKCVDGCSPYQLP-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229960001040 ammonium chloride Drugs 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 229940044197 ammonium sulfate Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical group OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- YMIFCOGYMQTQBP-UHFFFAOYSA-L calcium;dichloride;hydrate Chemical group O.[Cl-].[Cl-].[Ca+2] YMIFCOGYMQTQBP-UHFFFAOYSA-L 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940032296 ferric chloride Drugs 0.000 description 1
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 229960003390 magnesium sulfate Drugs 0.000 description 1
- 229940076230 magnesium sulfate monohydrate Drugs 0.000 description 1
- LFCFXZHKDRJMNS-UHFFFAOYSA-L magnesium;sulfate;hydrate Chemical compound O.[Mg+2].[O-]S([O-])(=O)=O LFCFXZHKDRJMNS-UHFFFAOYSA-L 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000009101 premedication Methods 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to an oral pharmaceutical composition containing dabigatran etexilate or a pharmaceutically acceptable salt thereof as active ingredient.
- Dabigatran etexilate (3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -1-methyl-1H-benzimidazole-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester) has the following chemical formula:
- This active ingredient is already known from WO 98/37075.
- the main indication field of said active ingredient is the postoperative prophylaxis of deep venous thromboses and the prophylaxis of strokes.
- the solubility of the active ingredient in water is only 1.8 mg/ml. Moreover, the active ingredient has a strong pH-dependent solubility that is greatly increased in the acidic environment. This leads to the problem that conventional oral pharmaceutical compositions have large variations in the bioavailability since the solubility of the active ingredient depends on the pH value in the patient's stomach. This is particularly problematic with patients in whom the stomach pH value is changed by physiological variability, illness, or premedications (for example, PP inhibitors). There is therefore a need for oral pharmaceutical compositions of the active ingredient dabigatran etexilate that provide a release that is independent from the pH value of the stomach and thus, provide bioavailability of the active ingredient.
- WO 03/074056 suggests a pharmaceutical composition for oral application that comprises in addition to the active ingredient one or more pharmaceutically acceptable organic acids having a water solubility of >1 g/250 ml at 20° C.
- the corresponding pharmaceutical compositions may cause incompatibilities in the patient.
- the addition of the organic acid restricts the possible amount of active ingredient in an appropriate tablet or capsule. This problem is further exacerbated by the fact that, as a rule, organic acids have only a low buffer capacity so that relatively large amounts of acid have to be added to cause a possible effect on the pH value of the ambience in dissolution of an appropriate tablet.
- the present invention relates to an oral pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, and an inorganic acidic excipient.
- the oral pharmaceutical composition therefore is better tolerated than the compositions known in the prior art since the inorganic acidic excipient is based on acids or salts that are already present in the body.
- inorganic acidic excipients often exhibit an only low molar weight so that the size of the dosage form can be reduced and the active ingredient load can be increased, respectively in comparison to conventional pharmaceutical compositions. This effect is enhanced by the fact that inorganic acidic excipients due to their high buffer capacity are able to absorb high intra-individual variations of the stomach pH value also in low amounts and thus, to ensure an uniform dissolution and influx of the active ingredient.
- the inorganic acidic excipient employed in the oral pharmaceutical composition according to the invention should have a pH value in a 1% aqueous solution of ⁇ 6, preferably a pH value in the range of from 1-4.
- a suitable inorganic acidic excipient can be any pharmaceutically acceptable excipient wherein it may be especially an inorganic acid or an inorganic acidic salt.
- the amount of the employed inorganic acidic excipient can be chosen by the skilled person such that in dissolution of the oral pharmaceutical composition an acidic pH value is adjusted in the environment of the active ingredient.
- the weight ratio of active ingredient to inorganic acidic excipient may be in the range of from 1:10 to 10:1.
- inorganic acidic excipients are inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid.
- in highly volatile acids such as hydrochloric acid it has proven to be advantageous if they are present also micro-encapsulated, adsorbed on a binder, or absorbed in a binder.
- Binders suitable for this are in particular polymers and silicic acid, especially pyrogenic silicic acid such as aerosil.
- the polymers there can be advantageously employed hydrophilic polymers and in particular water-soluble polymers having a water solubility of >0.01 mg/ml.
- Micro-crystalline cellulose is also suitable.
- hydrophilic polymer comprises polymers with polar groups.
- polar groups are hydroxy, amino, carboxy, carbonyl, ethers, esters, and sulfonates. Hydroxy groups are particularly preferred.
- the hydrophilic polymer has an average molecular weight in the range between 1000 and 250,000 g/mol, preferably 2000 and 100,000 g/mol, and particularly preferred between 4000 and 85,000 g/mol.
- a 2% (w/w) solution of the hydrophilic polymer in pure water has preferably a viscosity between 2 and 8 mPas at 25° C. The viscosity is determined in accordance to the European Pharmacopoeia (Ph. Eur.), 6 th edition, section 2.2.10.
- the hydrophilic polymer has preferably a glass transition temperature (Tg) between 20° C. and 220° C., preferably 25° C. to 160° C.
- the glass transition temperature (Tg) is the temperature at which the hydrophilic polymer becomes brittle on cooling and soft on heating. That means that the hydrophilic polymer becomes soft above the glass transition temperature and can be plastically deformed without breaking.
- the glass transition temperature is determined by means of a Mettler-Toledo® DSC 1 using a heating rate of 10° C./min. and a cooling rate of 15° C./min.
- hydrophilic polymers examples include cellulose derivatives, in particular hydrophilic derivatives of the cellulose (e.g. HPMC, HPC, carboxymethylcellulose, preferably as sodium or calcium salt, hydroxyethylcellulose, hydroxypropylcellulose), polyvinylpyrrolidone, preferably with a molecular weight of from 10,000 to 60,000 g/mol, copolymers of PVP, preferably co-polymers comprising vinylpyrrolidone and vinylacetate units (e.g.
- povidone, VA64, BASF preferably with a molecular weight between 40,000 and 70,000 g/mol
- the acid can for example be sprayed onto the binder or rather granulated, or the binder can be dispersed in a solution of the acid.
- a solution/suspension of acid and binder can be commonly spray dried or lyophilized, for example.
- an inorganic acidic salt may be used as the inorganic acidic excipient.
- inorganic acidic salt any pharmaceutically acceptable salt such as, for example hydrogen and dihydrogenphosphates, hydrogensulfates, ammonium chloride, ammonium sulfate, magnesium sulfate, magnesium chloride, ferrous chloride, ferric chloride, calcium chloride, and calcium sulfate is suitable.
- Hydrogen and dihydrogenphosphates and hydrogensulfates are in particular alkali or ammonium salts, especially sodium, potassium, and ammonium salts.
- the salts mentioned include their solvates, especially hydrates, such as for example magnesium chloride hexahydrate, calcium chloride mono or dihydrate, calcium sulfate dihydrate, magnesium sulfate monohydrate, and ferric chloride hexahydrate.
- the inorganic salt should be water-soluble, wherein water-soluble salts are those having a solubility of >0.01 mg/ml. Further, mixtures of one or more inorganic acids and/or one or more inorganic acidic salts can be employed in the oral pharmaceutical composition according to the invention.
- the inorganic acidic salt may either directly be mixed with the active ingredient and processed into appropriate pharmaceutical compositions or the salt can be prepared during the preparation of the pharmaceutical composition by adding an acid and a base.
- suitable amounts of phosphoric acid and sodium or potassium hydroxide may be added to obtain a potassium phosphate buffer as the inorganic acidic salt.
- the inorganic acidic salt may be present adsorbed on a binder or absorbed in a binder.
- Suitable binders are those mentioned above for the inorganic acids, wherein appropriate adsorbates and absorbates also may be obtained in accordance to the methods mentioned above for the inorganic acids.
- a particularly suitable pharmaceutically acceptable salt of the dabigatran etexilate is the mesylate salt, i.e. the salt of the methanesulfonic acid.
- the high buffer capacity and the low molar mass of the inorganic acidic excipients employed according to the invention permit the preparation of oral pharmaceutical compositions with a high active ingredient load.
- the oral pharmaceutical composition according to the invention contains more than 45% by weight, preferably more than 50% by weight dabigatran etexilate or a pharmaceutically acceptable salt thereof based on the total weight of the composition.
- the inorganic acidic excipient is present in a core material consisting of or containing the excipient and that the core material is surrounded by an active ingredient-containing layer. Additionally, the core material and the active ingredient-containing layer can be separated from each other by an interlayer. Correspondingly build up pharmaceutical compositions are described in WO 03/074056 in more detail.
- the oral pharmaceutical composition according to the invention may be present in the form of a capsule or a tablet.
- the pharmaceutical composition can contain one or more further pharmaceutically acceptable excipients such as e.g. fillers, lubricants, flow control agents, release agents, and disintegrants.
- excipients such as e.g. fillers, lubricants, flow control agents, release agents, and disintegrants.
- the pharmaceutical composition can contain one or more filler(s).
- a filler is a substance that increases the bulk volume of the mixture and thus the size of the resulting dosage form.
- Preferred examples of fillers are lactose and calcium hydrogenphosphate.
- the filler may be present in an amount of 0 to 80% by weight, preferred between 10 and 60% by weight of the total weight of the composition.
- Lubricants The function of the lubricant is to ensure that the pelletizing and the ejection take place without much friction between the solids and the walls.
- the lubricant is an alkaline-earth metal stearate or a fatty acid, such as stearic acid.
- the lubricant is present in an amount of 0 to 2% by weight, preferably between 0.5 and 1.5% by weight of the total weight of the pharmaceutical composition.
- Disintegrants Usually, by a disintegrant is meant a substance that is capable of breaking up the tablet into smaller pieces as soon as it is in contact with a liquid.
- Preferred disintegrants are croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (crospovidon) or sodium carboxymethyl glycolate (e.g. explotab) and sodium bicarbonate.
- the disintegrants is present in an amount of 0 to 20% by weight, preferably between 1 and 15% by weight of the total weight of the composition.
- Flow control agents As the flow control agent there can be used e.g. colloidal silica. Preferably the flow control agent is present in an amount of 0 to 8% by weight, more preferably in an amount between 0.1 and 3% by weight of the total weight of the composition.
- the release agent can be e.g. talcum and is present in an amount between 0 and 5% by weight, preferably in an amount between 0.5 and 3% by the weight of the composition.
- the present invention relates to a method for the preparation of an oral pharmaceutical composition as described above which comprises mixing the active ingredient with the inorganic acidic excipient and optionally after further processing steps compressing the mixture to tablets or filling the mixture into capsules.
- the inorganic acidic excipient is preferably micro-encapsulated, adsorbed onto a binder, or absorbed into a binder before mixing.
- the inorganic acidic excipient may be for example mixed in solution with the binder or the binder may be dissolved in the buffer solution and dried subsequently. Drying can be carried out by spray drying, lyophilization, or granulation onto a carrier.
- the inorganic acidic salts are dissolved in water and subsequently the pH value of the solution is adjusted to less than 3 with phosphoric acid.
- the polymer is dissolved and subsequently spray dried/lyophilized.
- the prepared intermediate is mixed with the active ingredient, filler, blasting agent, and flow improver for 15 min. on the tumbler. After adding the lubricant it is again mixed for 5 min.
- the final mixture can be compressed to tablets or filled into capsules.
- the active ingredient can already be added to the manufacturing process of the intermediates or the preparation may be transferred to a granule method.
- the pH controlled polymer solution was used to granulate filler and active ingredient.
- the dried granulate was sieved over 0.71 mm and subsequently mixed with disintegrant, flow improver for 15 min. on a tumbler. After adding the lubricant it was mixed for another 5 min.
- the final mixture can be compressed to tablets or alternatively filled into capsules.
- the inorganic acidic salt is dissolved in water and subsequently the pH value of the solution is adjusted to less than 3 with phosphoric acid. Subsequently, the solution is spray dried/lyophilized.
- the prepared intermediate is mixed with the filler, disintegrant, and flow improver for 15 min. on the tumbler. After adding the lubricant it is again mixed for 5 min. The final mixture can be compressed to tablets or filled into capsules.
- the active ingredient can already be added to the manufacturing process of the intermediate.
- All substances except the magnesium stearate are mixed for 15 min. in the tumbler. After adding the magnesium stearate it is mixed for another 5 min. The final mixture can be compressed to tablets or filled into capsules.
- Dabigatran etexilate mesylate 86.55 mg
- Povidon 25 15.00 mg
- An aqueous solution of Povidon 25 is adjusted to pH 1 with hydrochloric acid. With this granulation solution MCC is granulated in the fluid bed granulator. The dried granulate is mixed with Kollidon CL and Aerosil for 10 min. in the tumbler. After adding the magnesium stearate it is mixed for another 5 min. The final mixture can be compressed to tablets or filled into capsules.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP10155059 | 2010-03-01 | ||
EP10155059.8 | 2010-03-01 | ||
PCT/EP2011/052919 WO2011107427A1 (fr) | 2010-03-01 | 2011-02-28 | Composition pharmaceutique orale contenant du dabigatran etexilate |
Publications (1)
Publication Number | Publication Date |
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US20130052262A1 true US20130052262A1 (en) | 2013-02-28 |
Family
ID=43982233
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/582,183 Abandoned US20130052262A1 (en) | 2010-03-01 | 2011-02-28 | Dabigatran etexilate-containing oral pharmaceutical composition |
Country Status (13)
Country | Link |
---|---|
US (1) | US20130052262A1 (fr) |
EP (1) | EP2542224B1 (fr) |
JP (1) | JP5801826B2 (fr) |
CA (1) | CA2791561A1 (fr) |
CY (1) | CY1115556T1 (fr) |
DK (1) | DK2542224T3 (fr) |
EA (1) | EA201201202A1 (fr) |
ES (1) | ES2509117T3 (fr) |
IL (1) | IL221742A (fr) |
PL (1) | PL2542224T3 (fr) |
PT (1) | PT2542224E (fr) |
SI (1) | SI2542224T1 (fr) |
WO (1) | WO2011107427A1 (fr) |
Cited By (2)
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US20060183779A1 (en) * | 2002-03-07 | 2006-08-17 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof |
WO2019192195A1 (fr) | 2018-04-04 | 2019-10-10 | 上海汉都医药科技有限公司 | Composition pharmaceutique contenant du dabigatran étexilate et son procédé de préparation |
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ITMI20110445A1 (it) * | 2011-03-22 | 2012-09-23 | Lo Li Pharma Srl | Formulazione farmaceutica comprendente inositolo. |
CN103304539A (zh) * | 2012-03-07 | 2013-09-18 | 天津药物研究院 | 达比加群酯苹果酸盐及其制备方法和应用 |
EP2740471B1 (fr) | 2012-12-07 | 2015-05-27 | Hexal AG | Composition pharmaceutique orale comprenant le dabigatran etexilate |
IN2013CH05441A (fr) * | 2013-11-26 | 2015-05-29 | Aurobindo Pharma Ltd | |
IN2014MU01042A (fr) | 2014-03-26 | 2015-10-02 | Cadila Healthcare Ltd | |
CN105919962B (zh) * | 2015-12-18 | 2019-01-18 | 重庆两江药物研发中心有限公司 | 一种达比加群酯片剂及其制备方法 |
CN106491553A (zh) * | 2016-12-09 | 2017-03-15 | 吉林省博大伟业制药有限公司 | 一种甲磺酸达比加群酯的新合成工艺 |
JP2019014712A (ja) * | 2017-07-03 | 2019-01-31 | エルメッド エーザイ株式会社 | 安定なダビガトラン製剤 |
JP2021014411A (ja) * | 2019-07-10 | 2021-02-12 | 日医工株式会社 | 安定なダビガトランエテキシラート製剤 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060183779A1 (en) * | 2002-03-07 | 2006-08-17 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof |
US9925174B2 (en) * | 2002-03-07 | 2018-03-27 | Boehringer Ingelheim International Gmbh | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof |
WO2019192195A1 (fr) | 2018-04-04 | 2019-10-10 | 上海汉都医药科技有限公司 | Composition pharmaceutique contenant du dabigatran étexilate et son procédé de préparation |
US11707455B2 (en) | 2018-04-04 | 2023-07-25 | Shanghai Wd Pharmaceutical Co., Ltd | Pharmaceutical composition containing dabigatran etexilate and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
JP5801826B2 (ja) | 2015-10-28 |
DK2542224T3 (da) | 2014-10-20 |
EP2542224A1 (fr) | 2013-01-09 |
CA2791561A1 (fr) | 2011-09-09 |
PL2542224T3 (pl) | 2014-12-31 |
SI2542224T1 (sl) | 2014-10-30 |
WO2011107427A1 (fr) | 2011-09-09 |
ES2509117T3 (es) | 2014-10-17 |
CY1115556T1 (el) | 2017-01-04 |
PT2542224E (pt) | 2014-10-03 |
IL221742A (en) | 2015-09-24 |
EA201201202A1 (ru) | 2013-04-30 |
EP2542224B1 (fr) | 2014-08-13 |
JP2013521244A (ja) | 2013-06-10 |
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